BAG3 promotes tumour cell proliferation by regulating EGFR signal.pdf (3.08 MB)

BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer

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posted on 22.11.2019, 16:16 by Sarah Shields, Emer Conroy, Tony O'Grady, Alo McGoldrick, Kate Connor, Mark P. Ward, Zivile Useckaite, Eugene Dempsey, Rebecca Reily, Youe Fan, Anthony Chubb, Gomez-Matallanas, Elaine W. Kay, Darran P. O'Connor, Amanda McCann, William N. Gallagher, Judith A. Coppinger

Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC.

Funding

Science Foundation of Ireland, School of Biomolecular and Biomedical Sciences at University College Dublin. Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT.

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The original article is available at http://www.oncotarget.com

Published Citation

Shields S, Conroy E, O'Grady T, McGoldrick A, Connor K, Ward et al. BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer. Oncotarget. 2018;9(21):15673-15690

Publication Date

28/02/2018

Publisher

Impact Journals

PubMed ID

29644001

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